This invention relates generally to antimicrobial compounds and agents. More specifically, it concerns novel broad spectrum antimicrobial peptides containing a tryptophan triplet and their derivatives which exhibit antimicrobial activity with low immunogenicity. Also provided are methods of microbicidal or microbistatic inhibition of microbial growth using pharmaceutical and non-pharmaceutical compositions wherein such antimicrobial peptides are an active component.
Infectious diseases have plagued human populations throughout history and continue to cause millions of deaths each year. Although widespread use of vaccines and drug therapy has dramatically reduced mortality due to infectious disease in developed countries, infectious diseases continue to be the leading cause of death in third world countries. It is estimated that over 600 million people are infected with tropical diseases, resulting in some 20 million deaths each year. Even in developed countries, infectious disease organisms spread misery to untold millions each year.
Individuals with an immunodeficiency disease are particularly at risk for infectious disease. The basic clinical manifestations are frequent, prolonged, severe infections, which are often caused by organisms of normally low pathogenicity. The hallmarks of immunodeficiency disease are recurrent bacterial or fungal infections. The clinical manifestations range from mild skin infections to life-threatening systematic infections. Common infectious organisms include Staphylococcus aureas, Streptococcus pneumoniae, Escherichia coli, and various species of Pseudomonas, Candida, and Aspergillus. Because of the seriousness of many infectious diseases, scientists continue to search for effective means of killing or controlling such organisms which, at the same time, exhibit low immunogenicity.
It has been speculated that cathelin, a protein isolated from pig blood leukocytes, is the N-terminal fragment of a pig homolog of a novel family of antibacterial peptides. The cDNA sequence of a putative homolog of this proline/arginine-rich antibacterial porcine protein was described by Joze Pungercar, et al., "Molecular cloning of a putative homolog of proline/arginine-rich antibacterial peptides from porcine bone marrow," FEBS, 336:284-88 (1993). However, the potentially antimicrobial portion of this proposed 228-amino acid peptide is 101 amino acids long which is too long and too large for production and effective utilization as an antimicrobial agent.